Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis.

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. MATERIALS AND METHODS: We analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. RESULTS: Thirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-ß1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01-1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1-1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89-1, p = 0.036). CONCLUSION: We identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.

Decreased Patellar Fractures and Subluxation With Patellar Component Replacement at Stage-One Spacer.

BACKGROUND: Periprosthetic joint infection is a devastating complication of total knee arthroplasty and is often treated with 2-stage revision. We retrospectively assessed whether replacing the patellar component with articulating stage-one spacers was associated with improved outcomes compared to spacers without patellar component replacement. METHODS: A total of 139 patients from a single academic institution were identified who underwent an articulating stage-one revision total knee arthroplasty and had at least 1-year follow-up. Of the 139 patients, 91 underwent patellar component removal without replacement, while 48 had a patellar component replaced at stage-one revision. Patellar fracture and reinfection at any point after stage-one were recorded. Knee range of motion (ROM), patellar thickness, lateral tilt, and lateral displacement were measured at 6-weeks post stage-one. Chi-square, Fisher's exact, and t-tests were utilized for comparisons. There were no significant demographic differences between groups. RESULTS: Patellar component replacement at stage-one revision was associated with fewer patellar fractures (2.1 versus 12.1%, P = .046), less lateral patellar displacement (1.7 versus 16.0 mm, P < .01), and improved pre to postoperative knee ROM 6 weeks after stage-one (+5.9 versus -11.4°, P = .03). There was no difference in reinfections after stage-2 revision for the replaced or unreplaced patellar groups (15.4 versus 15%, P = 1.000). While the mean time between stage-one and stage-2 was not different (5.2 versus 4.5 months, P = .50), at one-year follow-up, significantly more patients in the patellar component replacement group were satisfied and refused stage-2 revision (45.8 versus 3.3%, P < .001). CONCLUSIONS: Replacing the patellar component at stage-one revision is associated with a decreased rate of patellar fracture and lateral patellar subluxation, improved ROM, and possible increased patient satisfaction, as reflected by nearly half of these patients electing to keep their spacer. There was no difference in reinfection rates between the cohorts.

Acute superior mesenteric artery syndrome complicated by severe gastric, pancreatic and renal ischaemia.

Superior mesenteric artery syndrome (SMAS) is a rare and potentially life-threatening cause of small bowel obstruction in which the superior mesenteric artery impinges on the third portion of the duodenum. SMAS is typically encountered in patients with low body fat and a history of rapid weight loss and is often diagnosed as a chronic or subacute condition. Here, we describe a case of a healthy adolescent boy without typical SMAS prodromal symptoms presenting with a severe, hyperacute proximal small bowel obstruction due to SMAS. Complications arising from massive gastric and duodenal distension, including gastric, pancreatic and renal ischaemia, necessitated emergent surgical intervention consisting of the duodenojejunostomy bypass with partial gastric resection. The patient recovered without significant lasting consequences.

A Pediatric Teletrauma Program Pilot Project: Improves Access to Pediatric Trauma Care and Timely Assessment of Pediatric Traumas.

BACKGROUND: Geographic location is a barrier to providing specialized care to pediatric traumas. In 2019, we instituted a pediatric teletrauma program in collaboration with the Statewide Pediatric Trauma Network at our level 1 pediatric trauma center (PTC). Triage guidelines were provided to partnering hospitals (PH) to aid in evaluation of pediatric traumas. Our pediatric trauma team was available for phone/video trauma consultation to provide recommendations on disposition and management. We hypothesized that this program would improve access and timely assessment of pediatric traumas while limiting patient transfers to our PTC. METHODS: A retrospective cohort study was conducted at the PTC between January 2019 to May 2023. All pediatric trauma patients age < 18 years who had teletrauma consults (TC) were included. We also evaluated all avoidable transfers without TC defined as admission for less than 36 hours without an intervention or imaging as a comparison group. RESULTS: A total of 151 TCs were identified: 62% male and median age of 8 years [IQR:4-12]. TC increased from 12 in 2019 to 100 in 2022-2023 and the number of partnering hospitals increased from 2 to 32. PH were 15-554 miles from the pediatric trauma center, with a median distance of 34 miles [IQR:28-119]. Following consultation, we recommended discharge 34%, admission 29%, or transfer to PTC 35%. Of those that were not transferred, 3% (3/97) required subsequent treatment at the PTC. Non-transferred TC had a higher percentage of TBI (61% vs 31%;p < 0.001) and were from farther, (40 miles[IQR:28-150] vs 30 miles[IQR:28-50];p < 0.001) compared to avoidable transferred patients without a TC. CONCLUSIONS: TC is a safe and viable addition to a pediatric trauma program faced with providing care to a large geographical catchment area. The pediatric teletrauma program provided management recommendations to 32 partnering hospitals and avoided transfer in approximately 63% of cases. LEVEL OF EVIDENCE: IV Treatment study.

Deep learning prediction of hospital readmissions for asthma and COPD.

QUESTION: Severe asthma and COPD exacerbations requiring hospitalization are linked to increased disease morbidity and healthcare costs. We sought to identify Electronic Health Record (EHR) features of severe asthma and COPD exacerbations and evaluate the performance of four machine learning (ML) and one deep learning (DL) model in predicting readmissions using EHR data. STUDY DESIGN AND METHODS: Observational study between September 30, 2012, and December 31, 2017, of patients hospitalized with asthma and COPD exacerbations. RESULTS: This study included 5,794 patients, 1,893 with asthma and 3,901 with COPD. Patients with asthma were predominantly female (n = 1288 [68%]), 35% were Black (n = 669), and 25% (n = 479) were Hispanic. Black (44 vs. 33%, p = 0.01) and Hispanic patients (30 vs. 24%, p = 0.02) were more likely to be readmitted for asthma. Similarly, patients with COPD readmissions included a large percentage of Blacks (18 vs. 10%, p < 0.01) and Hispanics (8 vs. 5%, p < 0.01). To identify patients at high risk of readmission index hospitalization data of a subset of 2,682 patients, 777 with asthma and 1,905 with COPD, was analyzed with four ML models, and one DL model. We found that multilayer perceptron, the DL method, had the best sensitivity and specificity compared to the four ML methods implemented in the same dataset. INTERPRETATION: Multilayer perceptron, a deep learning method, had the best performance in predicting asthma and COPD readmissions, demonstrating that EHR and deep learning integration can improve high-risk patient detection.

Association of Circulating Cardiomyocyte Cell-Free DNA With Cancer Therapy-Related Cardiac Dysfunction in Patients Undergoing Treatment for ERBB2-Positive Breast Cancer.

Importance: Cancer therapy-related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying early biomarkers of cardiotoxicity could facilitate an individualized approach to cardiac surveillance and early pharmacologic intervention. Circulating cell-free DNA (cfDNA) of cardiomyocyte origin is present during acute cardiac injury but has not been established as a biomarker of CTRCD. Objective: To determine whether circulating cardiomyocyte cfDNA is associated with CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy. Design, Setting, and Participants: A prospective cohort of 80 patients with ERBB2-positive breast cancer enrolled at an academic cancer center between July 2014 and April 2016 underwent echocardiography and blood collection at baseline, after receiving anthracyclines, and at 3 months and 6 months of ERBB2-targeted therapy. Participants were treated with doxorubicin-based chemotherapy followed by trastuzumab (+/- pertuzumab). The current biomarker study includes participants with sufficient biospecimen available for analysis after anthracycline therapy. Circulating cardiomyocyte-specific cfDNA was quantified by a methylation-specific droplet digital polymerase chain reaction assay. Data for this biomarker study were collected and analyzed from June 2021 through April 2022. Main Outcomes and Measures: The outcome of interest was 1-year CTRCD, defined by symptomatic heart failure or an asymptomatic decline in left ventricular ejection fraction (≥10% from baseline to less than lower limit of normal or ≥16%). Values for cardiomyocyte cfDNA and high-sensitivity cardiac troponin I (hs-cTnI) measured after patients completed treatment with anthracyclines were compared between patients who later developed CTRCD vs patients who did not using the Wilcoxon rank sum test, and the association of post-anthracycline cardiomyocyte cfDNA level with CTRCD was estimated using logistic regression. Results: Of 71 patients included in this study, median (IQR) age was 50 (44-58) years, all were treated with dose-dense doxorubicin, and 48 patients underwent breast radiotherapy. Ten of 71 patients (14%) in this analysis developed CTRCD. The level of cardiomyocyte cfDNA at the post-anthracycline time point was higher in patients who subsequently developed CTRCD (median, 30.5 copies/mL; IQR, 24-46) than those who did not (median, 7 copies/mL; IQR, 2-22; P = .004). Higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD (hazard ratio, 1.02 per 1-copy/mL increase; 95% CI, 1.00-1.03; P = .046). Conclusions and Relevance: This study found that higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD. Cardiomyocyte cfDNA quantification shows promise as a predictive biomarker to refine risk stratification for CTRCD among patients with breast cancer receiving cardiotoxic cancer therapy, and its use warrants further validation. Trial Registration: ClinicalTrials.gov Identifier: NCT02177175.

Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis.

PURPOSE: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP. METHODS AND MATERIALS: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual. RESULTS: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism. CONCLUSIONS: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP.

Experimental evidence of size-selective harvest and environmental stochasticity effects on population demography, fluctuations and non-linearity.

Theory and analyses of fisheries data sets indicate that harvesting can alter population structure and destabilise non-linear processes, which increases population fluctuations. We conducted a factorial experiment on the population dynamics of Daphnia magna in relation to size-selective harvesting and stochasticity of food supply. Harvesting and stochasticity treatments both increased population fluctuations. Timeseries analysis indicated that fluctuations in control populations were non-linear, and non-linearity increased substantially in response to harvesting. Both harvesting and stochasticity induced population juvenescence, but harvesting did so via the depletion of adults, whereas stochasticity increased the abundance of juveniles. A fitted fisheries model indicated that harvesting shifted populations towards higher reproductive rates and larger-magnitude damped oscillations that amplify demographic noise. These findings provide experimental evidence that harvesting increases the non-linearity of population fluctuations and that both harvesting and stochasticity increase population variability and juvenescence.

Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies.

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies inducing delayed cardiac inflammation following therapy due to activation of cGAS- and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING signaling in mice inhibits DNA damage-induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA-damaging therapies and effectively mitigates cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

Dog Bites in the United States from 1971 to 2018: A Systematic Review of the Peer-Reviewed Literature.

BACKGROUND: Surgical specialists in plastic, head and neck, hand, trauma surgery, and emergency medicine physicians bear the burden of treating the most serious injuries caused by animals. Most of these incidents result from an attack by a known dog, and breed has been proposed, but not proven, to be a controllable factor. The authors summarize the peer-reviewed literature on dog bites in the United States, specifically as related to the breeds implicated. METHODS: A systematic review of all peer-reviewed publications reporting on dog bites in the United States was performed. MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Library searches were conducted through May 8, 2018, for studies from the United States implicating a specific dog breed as responsible. RESULTS: Forty-one articles met inclusion criteria, the majority of which were single-institution retrospective reviews. Main outcomes were any dog bite reported in the peer-reviewed literature where a specific breed was implicated. Secondary measures included dog bites reported in areas where breed-specific legislation was enacted. The most common pure breed identified was German Shepherd, followed by Pit Bull-type breeds (i.e., American Staffordshire Terrier, American Pit Bull Terrier, Staffordshire Bull Terrier, American Bully), Labrador, Collie, and Rottweiler, respectively. Pit bull-type and German Shepherd breeds are consistently implicated for causing the most serious injuries to patients in the United States across heterogeneous populations, and this remained consistent across multiple decades. CONCLUSIONS: The authors' results indicate that German Shepherd and Pit Bull-type breeds account for the largest subset of pure breeds implicated in severe dog bites inflicted on humans in the medical literature. The role and complexity of mentioning breed in relation to human injuries are also discussed.

Anesthetic Considerations for Automated High-Frequency Jet Ventilation During Electromagnetic Navigation Bronchoscopy.

Newly advanced diagnostic bronchoscopic procedures, such as electromagnetic navigation bronchoscopy using navigation system technology (superDimension, Medtronic), provides computed tomography referenced and computerized 3-dimensional imaging. To increase accuracy and higher diagnostic biopsy yield, electromagnetic navigation bronchoscopy necessitates special anesthetic and ventilation techniques providing the interventional pulmonologist minimal respiratory lung motion. This anesthetic meets 2 important goals by limiting almost all interference from diaphragmatic and lung movement while allowing the anesthesia provider to achieve hands-free management. Proposed here is an anesthetic ventilation technique by automated high-frequency jet ventilation (HFJV) via double-lumen micro jet endotracheal tubes. This ventilation technique delivers consistent very low tidal volumes. Automated HFJV provides the pulmonologist the advantage of more accurate navigation and target alignment in this Global Positioning System-guided biopsy procedure. The technique offers essentially no chest motion, without interrupting ventilation. Additionally, HFJV allows the anesthetist better availability to attend to total intravenous anesthesia, adjustments, and interventions. The intention of this article is to detail an anesthetic method that provides a hands-free technique that requires only one anesthesia provider.

Risk of Unplanned Hospital Encounters in Patients Treated With Radiotherapy for Head and Neck Squamous Cell Carcinoma.

CONTEXT: Radiotherapy is highly effective for treating squamous cell carcinoma of the head and neck but is often associated with significant toxicities and severe morbidity. Unplanned emergency department (ED) visits and hospitalizations are common during treatment and come with a substantial financial and health burden as well as the potential for impaired long-term outcomes due to treatment disruption. OBJECTIVES: The objective of this study was to identify patient, disease, and treatment characteristics that were associated with ED encounters and admissions. METHODS: A cohort of 462 patients with cancer of the head and neck treated with radiotherapy at UT Southwestern between 2010 and 2015 was retrospectively analyzed. The risks of ED visits, admissions, multiple admissions, and extended admissions were determined. Risk factors for an unplanned hospital encounter were analyzed using univariate and multivariate logistic regression. RESULTS: Overall, 36% of patients had an unplanned hospital encounter during the treatment window. Patients with advanced disease, those with high comorbidity score, and those treated with concurrent chemotherapy were more likely to have unplanned admissions/ED visits. Social factors such as marital status, smoking status, and registration in the public hospital system were also strongly associated with admissions and multiple encounters. CONCLUSION: The high rate of admissions and ED visits emphasizes the importance of anticipating and managing toxicities during treatment. Social factors have a strong association with unplanned encounters and may present opportunities for targeted interventions to reduce admissions for patients at highest risk.

Limited Health Literacy Is Associated With Worse Patient-Reported Outcomes in Inflammatory Bowel Disease.

Background: Patients with inflammatory bowel disease (IBD) face complex health tasks and decisions. Limited health literacy is a risk factor for poor health outcomes, but this has not been examined in IBD. This study aims to assess the role of health literacy for patients with IBD. Methods: We prospectively enrolled adults with IBD receiving care from the Section of Gastroenterology at the Boston Medical Center. In-person, standardized questionnaires were administered to measure health literacy with the Newest Vital Sign, self-efficacy with the Medication Use and Self-Efficacy Scale, quality of life with the 10-question Short Inflammatory Bowel Disease Questionnaire, depression with the Patient-Reported Outcomes Measurement System Short Form, and clinical disease activity for patients with Crohn's disease with the Harvey-Bradshaw Index and for patients with ulcerative colitis with the Simple Clinical Colitis Activity Index (SCCAI). The relationships between health literacy and these variables were subsequently examined. Results: Of 112 patients invited to participate, 99 enrolled and completed the interview. Limited health literacy was identified in 40% (n = 40) of patients. Patients with limited health literacy reported significantly worse overall health (P = 0.03) and more depressive symptoms (P = 0.01). Of the 56 patients with Crohn's disease, those with adequate health literacy were more likely to be in clinical remission (mean Harvey-Bradshaw Index score < 5), compared with those with limited health literacy (odds ratio, 4.15; 95% confidence interval, 1.37 to 13.45; P = 0.01). There was no significant association between health literacy and clinical disease activity (SCCAI) in patients with ulcerative colitis. Conclusions: Limited health literacy is associated with lower ratings of subjective health and depression in IBD and more symptoms of active disease in patients with Crohn's disease.

Nuclear Localization of Apolipoprotein E4: A New Trick for an Old Protein.

One of the most important genetic risk factors for late-onset Alzheimer's Disease (AD) is harboring the ApoE4 allele. Much is known regarding the functions of the ApoE4 protein including cholesterol transport in the CNS and a critical role in clearing beta-amyloid deposits in the AD brain. However, recent studies demonstrating the nuclear localization suggest a novel function beyond the classical known actions of ApoE4. The purpose of the current review is to examine how this secreted protein traffics to the nucleus and to discuss possible outcomes of nuclear localization in the CNS. It is suggested that proteolytic fragmentation of ApoE4 is a key step leading to nuclear localization and the outcome of this event is to initiate transcription of various genes involved in inflammation and cell death. Therefore, the nuclear localization and induction of gene expression may provide a link between harboring the ApoE4 allele and enhanced dementia risk observed in AD.

Improved annotation of the insect vector of citrus greening disease: biocuration by a diverse genomics community.

Database URL: https://citrusgreening.org/.

A New Low-Temperature Electrochemical Hydrocarbon and NOx Sensor.

In this article, a new investigation on a low-temperature electrochemical hydrocarbon and NOx sensor is presented. Based on the mixed-potential-based sensing scheme, the sensor is constructed using platinum and metal oxide electrodes, along with an Yttria-Stabilized Zirconia (YSZ)/Strontium Titanate (SrTiO3) thin-film electrolyte. Unlike traditional mixed-potential sensors which operate at higher temperatures (>400 °C), this potentiometric sensor operates at 200 °C with dominant hydrocarbon (HC) and NOx response in the open-circuit and biased modes, respectively. The possible low-temperature operation of the sensor is speculated to be primarily due to the enhanced oxygen ion conductivity of the electrolyte, which may be attributed to the space charge effect, epitaxial strain, and atomic reconstruction at the interface of the YSZ/STO thin film. The response and recovery time for the NOx sensor are found to be 7 s and 8 s, respectively. The sensor exhibited stable response even after 120 days of testing, with an 11.4% decrease in HC response and a 3.3% decrease in NOx response.

Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors.

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and ß-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with ß-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and ß-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.